Prostaglandins are a family of biologically active compounds that are found in virtually all tissues and organs. These naturally occurring prostaglandis have extremely complex biological functions (e.g. stimulation of smooth muscles, dilation of smaller arteries and bronchi, lowering blood pressure, etc.). Synthetic prostaglandins are for example clinically used to induce childbirth or abortion, to prevent and treat peptic ulcers, to treat pulmonary hypertension, in treatment of glaucoma and ocular hypertension.
Prostaglandin F2α ((PGF2α-(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxyoct-1-enyl)cyclopentyl)hept-5-enoic acid)) has the structure shown below:

The PGF2α-derivatives are thus characterized by two hydroxyl groups in cis configuration relative to the cyclopentane ring, and two side chains in a trans configuration relative to each other. Analogs of PGF2α may have a different number of double bonds in the side chains and the substituents along the side chains as well as the length of the side chains may vary. The Z-configured double bond in the α-chain is a common feature in pharmaceutically active PGF2α analogs, whereas the double bond in the ω-chain may be missing (e.g. latanoprost and unoprostone). Particularly useful are derivatives with a co-chain bearing a phenyl substituent and wherein the α-chain is an ester or an amide.
Examples for such PGF2α derivatives having therapeutic use are latanoprost (general formula (II)), travoprost (general formula (III)), and bimatoprost (general formula (I)). Bimatoprost, in contrast to latanoprost and travoprost, has an amide function, which influences the polarity of the molecule in a way that purification strategies utilized for latanoprost and travoprost can not be applied.

PGF2α-analogs for use in treatment of glaucoma and ocular hypertension are described for example in EP 0 364 417 A1 (Pharmacia AB). In EP 0 364 417 A1, a number of PGF2α-analogs with variations in the ω-chain are described. The synthesis disclosed follows the original route of Corey et al. (Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675-5677; Corey, E. J.; Noyori, R.; Schaaf, T. K. J. Am. Chem. Soc. 1970, 92, 2586-2587) with some modifications and is shown in scheme 1 for the preparation of 17-phenyl-18,19,20-trinor-PGF2α-isopropy ester.
The starting material disclosed in EP 0 364 417 A1 is commercially available p-phenyl-benzoyl (PPB) protected Corey lactone (1), which is converted into the corresponding aldehyde (2) by oxidation using DCC/DMSO. Compound (2) is not isolated but reacted in solution with an appropriate phosphonium salt to give intermediate (3). Reduction of the ketone in compound (3) forms the corresponding alcohol (4) as a mixture of diastereomers. After deprotection to form diol (5) the lactone is selectively reduced to the lactol (6) which was purified using column chromatography. A subsequent Wittig reaction forms acid (7) which is converted into the desired product (8) by esterification using isopropyl iodide.

In WO 94/06433 (Allergan) the conversion of acid (7) to bimatoprost using a two step synthesis is described. The first step is an esterification using methyl iodide, which is followed by an amide formation using ethylamine (scheme 2).

An improved synthesis for such 13,14-dihydro PGF2α-analogs is described in U.S. Pat. No. 5,359,095 (Pharmacia AB; scheme 3). As the original reduction of the ketone 3 only gave 37% yield of the desired 15S-alcohol (9), L-selectride was used as reducing agent, improving the diastereoselectivity of the reduction and increasing the yield of (9) to 60%. Additionally, it had been found that the allylic alcohol in compound (9) is deoxygenated on hydrogenation of the double bond over palladium catalyst. Therefore, protection of the allylic alcohol (as tetrahydropyranylether) seemed to be necessary.
However, this sequence for the preparation of latanoprost involves two additional steps (protection/deprotection) and insufficiently solves the problem regarding the diastereoselectivity of the reduction from (3) to (9). The synthesis of bimatoprost is not disclosed in this patent application.

In U.S. Pat. No. 5,698,733 (Alcon) a further process for the stereoselective reduction of benzoyl-protected enone (16) is described using (−)-B-chlorodiisopinocamphenylborane [(−)-DIP-Cl]. The desired 15S-alcohol (17), which is the chemical equivalent of compound (9), is obtained with a diastereomeric excess (de) of 92% (scheme 4).

International patent application WO 2006/094294 (Teva) describes another methodology to deplete the unwanted 15R-isomer using enzymatic acylation or enzymatic ester hydrolysis.
Patent applications WO 2002/096898 (Resolution Chemicals) and US 2007/0167641 (Chirogate) describe the use of silyl protecting groups in the preparation of PGF2α-analogs.
Patent applications WO 01/55101 (Finetech) and WO 2002/096868 (Finetech) make of use of THP (tetrahydropyranyl) or THP and PPB (p-phenyl-benzoyl) protecting groups and describe the recovery of the unwanted C-15 epimer by an oxidation-reduction sequence.
In WO 2003/074481 (Allergan) the coupling of protected lactol (18) with heptanoic derivative (23) is described (scheme 5, Z represents a protecting group and the dotted line in the formula represents the presence or absence of a double bond). The advantage of the invention is that the complete α-side chain is introduced in one step. However, as no experimental details are given the process can not be compared with the prior art. It is mentioned that impurities in crude bimatoprost are limited to less than 8% thereby suggesting a high level of impurities generated during the process. The process requires the use of protecting groups making the reaction sequence lengthy.

The processes described in the state of the art have the drawback that the α-chain is introduced using the Wittig reagent derived from 5-triphenylphosphoniopentanoic acid to give the corresponding acid which has to be converted into an ester or an amid in a further step to obtain the desired compound. In the case of bimatoprost, the introduction of the amide functionality out of the corresponding acid needs two steps and requires long reaction times or that elaborate protecting group strategies are used. The isolation of many intermediates is necessary and the process is laborious and less efficient. Furthermore, bimatoprost is obtained in insufficient purity.